Post-Streptococcal Glomerulonephritis

Bernardo Rodriguez-Iturbe, MD 1 and Mark Haas, MD, PhD2

Created: February 10, 2016.

Abstract
Acute glomerulonephritis that results from streptococcal infections is the best-studied
immune complex-mediated glomerulonephritis. Initially described in the convalescence
of scarlet fever, the incidence of acute post streptococcal glomerulonephritis (APSGN) has
decreased worldwide, particularly in developed countries where it is now rare and is
limited to adult patients who have debilitating conditions. In developing countries, the
annual burden of APSGN remains at a level of least 9 cases per 100,000 inhabitants. Two
antigenic fractions of the streptococcus (streptococcal GAPDH/nephritis-associated
plasmin receptor, and streptococcal pyrogenic exotoxin B and its zymogen precursor) are
currently under scrutiny as putative nephritogens. Glomerulonephritis results from the
glomerular deposition of circulating immune complexes and by the in situ formation of
immune complexes. In-situ formation of immune complexes is a characteristic associated
with cationic antigens that have a charge-facilitated penetration through the polyanionic
glomerular basement membrane. The plasmin-binding capacity of streptococcal antigens
favors immune complex deposition and inflammation. The typical pathological changes
are endocapillary proliferation with varying degrees of leukocyte infiltration, and C3, IgG,
and IgM immune deposits. Electron microscopy shows the hallmark lesion of
subepithelial electron dense deposits (“humps”). The immediate prognosis is excellent in
children, but adults have a significant early mortality, which partially results from
cardiovascular disease. The long-term development of end-stage renal disease is
exceptional in children. However, studies in aboriginal communities indicate that patients

1 Nephrology Service, Hospital Universitario de Maracaibo, Universidad del Zulia and Instituto
Venezolano de Investigaciones Científicas (IVIC)-Zulia, Maracaibo, Venezuela; Email:
brodrigueziturbe@gmail.com. 2 Department of Pathology and Laboratory Medicine, Cedars-
Sinai Medical Center, Los Angeles, California, USA; Email: mark.haas@cshs.org.

Corresponding author.

NLM Citation: Rodriguez-Iturbe B, Haas M. Post-Streptococcal Glomerulonephritis. 2016 Feb 10.

In: Ferretti JJ, Stevens DL, Fischetti VA, editors. Streptococcus pyogenes : Basic Biology to
Clinical Manifestations [Internet]. Oklahoma City (OK): University of Oklahoma Health Sciences
Center; 2016-.

© The University of Oklahoma Health Sciences Center

Except where otherwise noted, this work is licensed under a Creative Commons Attribution-
NonCommercial-NoDerivatives 4.0 International License (CC-BY-NC-ND 4.0). To view a copy of
this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
2 Streptococcus pyogenes

with a history of APSGN have a higher incidence of albuminuria, and that APSGN
represents a risk factor for the subsequent development of chronic renal failure, if
associated with diabetes and obesity.

Introduction
Acute poststreptococcal glomerulonephritis (APSGN) is the prototype of post-infectious
glomerulonephritis and is associated with a previous skin or throat infection by group A
streptococcus (Streptococcus pyogenes), or occasionally groups C or G streptococcus.
According to Becker and Murphy (Becker & Murphy, 1968), the development of dark and
scanty urine was a feared complication of the epidemics of scarlet fever in the fourteenth
century, and clinical descriptions of the “dropsy that follows scarlet fever” have appeared
in medical literature since at least 1812 (Wells, 1812). APSGN was probably the cause of
death of Wolfgang Amadeus Mozart in 1791 (Zegers, Weigl, & Steptoe, 2009).
The observation that the disease appeared in the convalescent period of scarlet fever led
Clemens von Pirquet (von Pirquet, 1911) to postulate that post-scarlatinal nephritis was
caused by the development of harmful antibodies (as opposed to the beneficial antibodies
in vaccination) and coined the term “allergy” (altered reactivity) to define this pathogenic
modality. This landmark paper opened the field of immune complex-mediated diseases.
The demonstration of the streptococcal etiology of scarlet fever (Dochez & Sherman,
1924) and the recognition that acute rheumatic fever and glomerulonephritis, both
complications of streptococcal infections, have epidemiological and biological differences
and rarely, if ever, occur in the same patient; this suggested the existence of
rheumatogenic and nephritogenic strains of the bacterium to Seegal and Earle (Seegal &
Earle, 1941), and prompted the search for nephritogenic antigens (reviewed in
(Rodríguez-Iturbe & Batsford, 2007)).

Epidemiology
APSGN may occur in epidemic outbreaks or in clusters of cases, and it may occur in
isolated patients. Epidemic outbreaks reported in the past as a consequence of upper
respiratory or skin streptococcal infections have periodically appeared in specific regions
of the world, such as the Red Lake Indian Reservation in Minnesota (Anthony, Kaplan,
Wannamaker, Briese, & Chapman, 1969); in Port of Spain, Trinidad (Poon-King, et al.,
1967); in Maracaibo, Venezuela (Rodríguez-Iturbe, 1984); and in the Northern Territory
of Australia (Marshall, et al., 2011). The most recent epidemics have occurred in the
indigenous communities of the Northern Territory of Australia, resulting from pyoderma
after infection with emm55 group A streptococcus (Marshall, et al., 2011) and in the rural
region of Nova Serrana, Brazil, caused by the ingestion of unpasteurized milk obtained
from cows with mastitis caused by Streptococcus zooepidemicus (Balter, et al., 2000).
Streptococcus zooepidemicus has also caused clusters of cases (5–15 patients) reported in
the last two decades in poor communities in industrialized countries (Nicholson, et al.,
2000).
Post-Streptococcal Glomerulonephritis 3

In recent decades, the incidence of APSGN has declined significantly worldwide. The
reduction of the incidence of APSGN is probably the result of easier and earlier access to
appropriate medical care for streptococcal infections. Reports from France (Simon, et al.,
1994), Italy (Coppo, Gianoglio, Porcellini, & Maringhini, 1998), China (Zhang, Shen,
Feld, & Stapleton, 1994), Chile (Berríos, et al., 2004), Singapore (Yap, et al., 1990), the
United States (Roy & Stapleton, 1990), and Venezuela (Rodríguez-Iturbe & Musser, 2008)
all indicate that APSGN is now an infrequent disease, and its rarity in affluent societies
has been considered a factor for delayed diagnosis in patients who do not have gross
hematuria (Pais, Kump, & Greenbaum, 2008).
In industrialized countries, APSGN is now a disease of elderly patients that tend to have
debilitating conditions, malignancy, alcoholism, or diabetes (Montseny, Meyrier,
Kleinknecht, & Callard, 1995). Nevertheless, APSGN remains a significant health problem
in underdeveloped societies. Endocapillary glomerulonephritis, assumed to be of
poststreptococcal etiology, is the most common glomerulonephritis found in children in
developing countries (Rodríguez-Iturbe & Mezzano, 2005) and in aboriginal populations
(Currie & Brewster, 2001). Two independent studies have estimated the incidence of
APSGN in developing countries. Carapetis et al. (Carapetis, Steer, Mulholland, & Weber,
2005) analyzed 11 population studies and found that the annual burden of APSGN in
developing countries was 9.3 cases per 100,000 people. We evaluated the incidence of
APSGN in developing countries, using the reports of pediatric acute renal failure due to
glomerulonephritis (Rodríguez-Iturbe & Musser, 2008). We assumed that the cases of
acute glomerulonephritis were in fact APSGN, which was explicitly stated in most series,
but not in all. These patients had severe renal failure because they were seen at a referral
hospital and admitted to the intensive care unit, if one was available, and then dialyzed.
The total number of cases in the general population was estimated, considering that
uncomplicated cases of APSGN are 100 to 300 times more common than those of life-
threatening disease. Using this approach, the annual incidence of APSGN in developing
countries was estimated to be 9.5 (low estimate) to 28.5 (high estimate) cases per 100,000
people. This low value is remarkably close to the estimate of Carapetis et al. (Carapetis,
Steer, Mulholland, & Weber, 2005) and the higher value exceeds it by three-fold—yet,
these authors acknowledged that theirs was likely an underestimation and that the actual
incidence was probably a great deal higher.

Etiology and pathogenesis

APSGN is an immune complex-mediated disease. Several mechanisms may participate in
the pathogenesis of renal damage (Table 1). Nephritogenic immune complexes are formed
in circulation and deposited in the glomeruli; alternately, the antigen and antibody arrive
separately and meet in or outside the glomerular basement membrane, causing in situ
immune complex disease. Immune cell recruitment, production of chemical mediators
and cytokines, and local activation of the complement and coagulation cascades drive an
inflammatory response that is localized in the glomeruli. Glomerular deposition of
circulating immune complexes depends on the antigen load, the antigen:antibody ratio,
4 Streptococcus pyogenes

and the size of the immune complexes (Dixon, Feldman, & Vazquez, 1961; Germuth,
Senterfit, & Dreesman, 1972). In situ formation of immune complexes is favored by
cationic antigens that have a charge-dependent facilitated penetration into the
polyanionic glomerular basement membrane, and tend to occur in conditions of antigen
excess (Vogt, et al., 1990).

Table 1. Pathogenetic mechanisms participating in acute poststreptococcal glomerulonephritis

Mechanism
Nephritogenic antigens (NAPlr,
SPEB, streptokinase, others)
Circulating immune complexes
In situ Immune complexes (cationic SPEB co-localized with
antigens)
Evidence
NAPlr and SEPB demonstrated in
renal biopsies
Circulating anti-SPEB and anti-
NAPlr antibodies in APSGN
patients
complement in glomeruli and
demonstrated in the subepithelial 2005)
electron-dense deposits (“humps”)
in APSGN
Reference
(Oda, et al., 2010; Poon-King,
Bannan, Viteri, Cu, & Zabriskie,
1993; Nordstrand, McShan,
Ferretti, Holm, & Norgren,
2000)
(Yoshizawa, et al., 2004; Parra,
et al., 1998)
(Batsford, Mezzano, Mihatsch,
Schlitz, & Rodríguez-Iturbe,

Autoimmunity (anti-IgG, other) Neuraminidase is produced by (Mosquera & Rodríguez-Iturbe,

Anti-Ig ( induced by the loss of
sialic acid of the IgG or binding of Renal anti-IgG deposits
the Fc fragment of IgG to type II
receptors on the surface of group A
streptococcus)
Other autoimmune reactivity
some nephritogenic streptococci.
Serum neuraminidase activity in
APSGN patients
Serum anti-IgG titers
Anti-DNA, anti.C1q, ANCA
demonstrated in serum
1984; Rodríguez-Iturbe,
Katiyar, & Coello, 1981; Asami,
Tanaka, Gunji, & Sakai, 1985)
(Rodríguez-Iturbe B. , 1984;
Parra, et al., 1998; Rodríguez-
Iturbe, Rabideau, García, &
McIntosh, 1980; Burova, et al.,
2012)
(Kozyro, et al., 2006; Ardiles,
Valderrama, Moya, & Mezzano,
1997)

Other
Increased plasmin activity in Co-localization of plasmin and (Yoshizawa, et al., 2004; Oda, et
glomeruli (facilitating immune NAPlr in glomeruli. Increased al., 2010; Oda, et al., 2008)
complex deposition urinary plasmin activity
Neuraminidase-induced glomerular Desialised leukocytes accumulate (Mosquera & Rodríguez-Iturbe,
infiltration of desialised leukocytes in the glomeruli of patients with 1986; Marín, Mosquera, &
APSGN Rodríguez-Iturbe, 1995)
Post-Streptococcal Glomerulonephritis 5

Nephritogenic antigens
Traditionally, APSGN was considered to be caused by an antigen present in group A
streptococci. Streptococcus pyogenes of M types 1, 2, 4, and 12 were associated with
epidemic nephritis resulting from upper respiratory infections and M types 47, 49 and 55
were associated with epidemic nephritis following pyoderma. However, nephritis may also
follow infections with group C streptococci since Str. zooepidemicus has been identified as
the cause of an epidemic in Brazil (Balter, et al., 2000) and several clusters of cases
(Nicholson, et al., 2000; Francis, Nimmo, Efstratiou, Galanis, & Nuttall, 1993); therefore
nephritogenic antigen(s) are present in streptococci from several groups.
Throughout the years, many putative streptococcal nephritogenic antigens have been
studied without definite confirmation of their causal relationship with glomerulonephritis
(Rodríguez-Iturbe & Batsford, 2007).
The nephritogenic potential of streptokinase was investigated by Nordstrand et al.
(Nordstrand, Norgren, Ferretti, & Holm, 1998) in mice with the experimental tissue cage
model, and demonstrated glomerular streptokinase deposits in association with
hypercellularity, complement deposition, and proteinuria. Subsequent studies by this
group evaluated allelic variants of streptokinase using site-specific integration plasmids,
and demonstrated the nephritogenic properties of the nephritis-associated streptokinase
gene ska I(Nordstrand, McShan, Ferretti, Holm, & Norgren, 2000).
Presently, two streptococcal antigenic fractions with substantial claims to nephritogenicity
are being actively investigated. These are the nephritis associated plasmin receptor
(NAPlr), identified as glyceraldehyde 3-phosphate dehydrogenase (GAPDH) (Oda, et al.,
2010; Yoshizawa, et al., 2004), and the streptococcal pyrogenic exotoxin (erythrotoxin) B
(SPEB) and its zymogen precursor (zSPEB) (Poon-King, Bannan, Viteri, Cu, & Zabriskie,
1993; Vogt, Batsford, Rodríguez-Iturbe, & García, 1983).
Work by Fujino et al. (Fujino, et al., 2007) has shown that the expression and gene
sequence of NAPlr is present in streptococci from several groups. Anti- NAPlr antibody
levels are found in 92% of the sera from convalescent APSGN patients and in 60% of the
uncomplicated streptococcal infections in Japan (Yoshizawa, et al., 2004). NAPlr is present
in early biopsies of APSGN and, since it is not co-localized with complement or IgG, its
role as a nephritogen is thought to be related to its plasmin-binding capacity, which
facilitates immune complex deposition and inflammation (Oda, et al., 2010). The
nephritogenic potential of plasmin-binding activity has been noted, not only in NALPr
but also in SPEB, streptokinase, and enolase. Oda et al. (Personal communication,
discussed in (Rodríguez-Iturbe & Musser, 2008)) remarked that this property may
represent a common nephritogenic property of both NALPr and SPEB, since both of these
antigens were identified by their group in the mesangium of biopsies of APSGN. Along
with this possibility, patients with APSGN exhibit an increase in urinary plasmin-like
activity (Oda, et al., 2010; Oda, et al., 2008).
6 Streptococcus pyogenes

SPEB, an extracellular cysteine proteinase, is a cationic (pK>8.0) antigen that is co-

localized in the glomeruli with complement and Ig deposits, and is the only streptococcal
antigen that has been demonstrated within the electron dense subepithelial deposits
(humps) that are the hallmark of APSGN (Batsford, Mezzano, Mihatsch, Schlitz, &
Rodríguez-Iturbe, 2005). It is likely that this localization is facilitated by the cationic
charge of this antigen, as earlier studies have postulated (Vogt, et al., 1990; Vogt, Batsford,
Rodríguez-Iturbe, & García, 1983). High anti-SPEB/zSPEB antibody titers have been
found in the vast majority of convalescent sera sampled from patients in Latin America
(Parra, et al., 1998). SPEB/zSPEB induces chemotaxis and increases angiotensin II
production by mesangial cells (Romero, Mosquera, Novo, Fernandez, & Parra, 1999;
Viera, Pedreanez, Rincon, & Mosquera, 2009). Recent studies have demonstrated that the
Fc portion of antibodies directed to SPEB bind to the C-terminal domain (rSPEB
345-398), and that immunization with this domain prevents group A streptococcal
infection in mice (Tsao, et al., 2013). The attractiveness of a charge-related GBM
penetration in the pathogenesis of APSGN (Oite, Batsford, Mihatsch, Takamiya, & Vogt,
1982) has led Zhang et al. (Zhang, Ignatowski, Spengler, Noble, & Stinson, 1999) to
examine if histones that are cationic elements may be part of the pathogenesis of APSGN.
Their studies showed that histones enter the circulation after streptococcal lysis and are
capable of inducing in situ immune-complex formation.
Finally, recent evidence suggests that there is not a single nephritogenic antigen, since
studies by Beres et al. (Beres, et al., 2008) have shown that the gene that encodes for SPEB
was absent in the Str. zooepidemicus isolated from patients in the Brazil epidemic, and
therefore that this antigenic fraction was not involved in this epidemic. Notably, in studies
of the Str. zooepidemicus of the Brazil epidemic, Nicholson et al. (Nicholson, et al., 2000)
found that 33 of 44 patients were seropositive for the Szp5058 fusion protein that was
isolated from the causative streptococcal strain, and noted that the antiphagocytic
properties of Szp proteins may play a role in the pathogenesis of glomerulonephritis.
Both NALPr and SPEB are capable of inducing monocyte chemoattractant protein 1
(MCP1) and IL-6 in mesangial cells (Khan, et al., 2007; Pedreanez, Viera, Rincon, &
Mosquera, 2006; Rincon, Viera, Romero, & Mosquera, 2003) and SPEB elicits the release
of a variety of cytokines and interleukins from peripheral blood leucocytes (Viera,
Pedreanez, Rincon, & Mosquera, 2007).

Humoral and cellular immunity

Activation of the complement system is a consequence of the antigen/antibody reactivity
found in glomeruli. The alternate pathway of complement activation is usually activated
in APSGN and is manifested by a depression of C3 levels. However, some patients may
also have a reduction in their levels of C1 and C4. In these patients, there may be a role for
Protein H, a surface streptococcal protein that may activate the classic pathway of
complement activation, in combination with IgG (Berge, Kihlberg, Sjöholm, & Björck,
1997). In addition, in some patients, there may also be complement activation by the
lectin pathway (Ohsawa, et al., 1999); but APSGN may develop in individuals who are
Post-Streptococcal Glomerulonephritis 7

genetically unable to activate this pathway (Skattum, Akesson, Truedsson, & Sjöholm,
2006).
In addition to humoral immunity, cellular immune mechanisms are also activated in
APSGN. It has long been known that there is an overexpression of cellular adhesion
molecules (ICAM-1, LFA-1) and infiltration of lymphocyte and macrophages in the
glomeruli of these patients. (Parra, Platt, Falk, Rodríguez-Iturbe, & Michael, 1984; Parra,
Romero, Henriquez-La Roche, Pineda, & Rodríguez-Iturbe, 1994). Higher numbers of
CD4-positive lymphocytes are present in renal biopsies obtained in the first 3–4 weeks of
the disease and decrease afterwards (Parra, Platt, Falk, Rodríguez-Iturbe, & Michael,
1984). Increased glomerular expression of IL-8 correlates with neutrophil infiltration and
transforming growth factor–β with mesangial expansion (Mezzano, Burgos, Olavarría, &
Caorsi, 1997).

Autoimmune reactivity
High titers of anti-IgG rheumatoid factors have been reported in as many as two-thirds of
the patients with APSGN in the first week of the disease (Rodríguez-Iturbe, 1984), and
anti-human IgG deposits within the glomeruli are present in 29% of the biopsies
(Rodríguez-Iturbe, 2008) and were eluted from the kidney of a fatal case of the disease
(Rodríguez-Iturbe, Rabideau, García, & McIntosh, 1980). This anti-IgG reactivity may be
due to autoantigenic changes to IgG modified by neuraminidase (sialidase). Using
methods that measure the release of acetyl neuraminic acid from substrates by a
thiobarbituric acid assay, neuraminidase activity was found in group A and B streptococci
and, more specifically, in streptococcal strains isolated from patients with nephritis
(Mosquera & Rodríguez-Iturbe, 1984). However, a more sensitive methylumbelliferyl
acetyl neuraminidase fluorescence test failed to demonstrate neuraminidase activity in
culture supernatants of a large number of Streptococcus pyogenes strains (Savic & Ferretti,
1994). Neuraminidase activity and free sialic acid have been found in the plasma of
patients with acute APSGN (Asami, Tanaka, Gunji, & Sakai, 1985; Rodríguez-Iturbe,
Katiyar, & Coello, 1981; Rodríguez-Iturbe, Rubio, & García, 1981). The existence of sialic
acid depleted glomerular structures was investigated through the glomerular binding
capacity of the lectin Arachis Hypogaea (peanut agglutinin), a lectin with a highly specific
affinity for galactopyranosyl galactosamine radicals that are exposed after sialic acid
removal. Positive intraglomerular staining with this FITC-lectin was detected in the
majority of early APSGN biopsies. (Mosquera & Rodríguez-Iturbe, 1986). Neuraminidase
may have the additional effect of facilitating the infiltration of desialized leucocytes in the
glomeruli (Marín, Mosquera, & Rodríguez-Iturbe, 1995). The simultaneous presentation
of APSGN and thrombotic microangiopathy was considered to be the result of
streptococcal neuraminidase (Duvic, Desramé, Hérody, & Nédélec, 2000).
Another possible mechanism for the production of anti-Ig is the binding of the Fc
fragment of IgG to type II receptors on the surface of group A streptococcus. This binding
induces intense anti-IgG reactivity and glomerulonephritis with anti-IgG deposits, which
may have nephritogenic potential (Burova, et al., 2012; Burova, et al., 1998).
8 Streptococcus pyogenes

Other autoimmune phenomena that have been reported in patients with APSGN include
anti-DNA antibodies, anti-C1q antibodies (Kozyro, et al., 2006), and antineutrophil-
cytoplasmic autoantibodies (ANCAs). ANCAs have been found in two-thirds of the
patients with azotemia, and in 70% of the patients with crescentic APSGN and a rapidly
progressive course (Ardiles, Valderrama, Moya, & Mezzano, 1997). Despite the variety of
findings of autoimmune reactivity, the clinical relevance of these phenomena remains
undefined in APSGN.

Genetic aspects
The familial incidence of APSGN was noted in one of the earliest descriptions of the
disease. In 1812, Wells (Wells, 1812) noted that “when one child of a family has been
attacked with this disease, the other children of the same family who passed through
scarlet fever are more liable to become dropsical, than the children of another family, who
had also labored under that fever but among whom no instance of dropsy has occurred,”
and attributed this predisposition to “similarity of constitution derived from common
parents.” Subsequent studies have shown that the attack rate of APSGN in the general
population in epidemic situations ranges between 5% and 28%, while the development of
APSGN (clinical and subclinical) in siblings of index cases in non-epidemic conditions is
38% (Rodríguez-Iturbe, Katiyar, & Coello, 1981). Studies by Layrisse et al. (Layrisse,
Rodríguez-Iturbe, García-Ramírez, Rodríguez, & Tiwari, 1983) suggested that DR4 HLA
antigens were more common in unrelated patients with APSGN, and investigations in
Japan (Naito, Kohara, & Arakawa, 1987) reported association between DR1 antigens and
APSGN. Nevertheless, the genetic characteristics that are responsible for predisposition
(or resistance) to the disease have not been identified.

Clinical and serological characteristics

As previously indicated, APSGN in developed countries is now a disease of patients with
chronic debilitating diseases. The clinical characteristics and the prognosis in these
patients are different from the milder clinical course in children. In children with APSGN
massive proteinuria and cardiovascular complications are rare and early mortality
exceptional. In elderly individuals with APSGN, proteinuria in the nephrotic range occurs
in 20% of the patients, congestive heart failure in 43%, and azotemia in 83% (Melby,
Musick, Luger, & Khanna, 1987).
The classic patient with APSGN is a child (the male:female ratio is 2:1) between the ages
of 2 and 18. The latent period between upper respiratory infection and nephritis is 7–10
days and 2–4 weeks in cases that follow skin infection. The typical clinical presentation is
of acute nephritic syndrome (hematuria, edema, hypertension, and oliguria); in a
minority of cases, APSGN may be manifested by nephrotic syndrome; and in rare cases,
by a rapidly progressive (crescentic glomerulonephritis) clinical course. In a typical case of
post-streptococcal nephritis, improvement is observed after 2–7 days when the urine
volume increases, followed rapidly by resolution of edema and return of the blood
pressure to normal levels. Asymptomatic disease may be manifested by microscopic
Post-Streptococcal Glomerulonephritis 9

hematuria and a fall in serum complement levels, and is 4–5 times more common than
clinical disease in non-epidemic conditions (Rodríguez-Iturbe, Katiyar, & Coello, 1981;
Dodge, Spargo, & Travis, 1967).
The most consistent serological finding in the acute period is a reduction in serum
complement levels, which return to normal levels in less than a month. In the first week of
the disease, high rheumatoid factor titers and cryoglobulins may be found in as many as
two-thirds of the patients (Rodríguez-Iturbe, 1984). The best markers for nephritogenic
streptococcal infection are serum antibody levels to NALPr (Yamakami, et al., 2000) or
SPEB/zSPEB (Parra, et al., 1998), but these determinations are not generally available.
Since positive cultures are not always obtained, antistreptococcal antibody titers are
usually used to demonstrate the existence of an antecedent streptococcal infection.
Antistreptolysin O titers and anti-DNase B titers are the most frequently elevated in upper
respiratory infections and pyodermitis, respectively. A streptozyme test that includes 4
major antigens (DNase B, Streptolysin O, hyaluronidase and streptokinase) is reported to
be positive in more than 80% of the cases (Rodríguez-Iturbe, 1984).
Renal biopsy is seldom performed in uncomplicated cases of APSGN in children with a
typical clinical picture, particularly in epidemic situations. Biopsy is usually done in adult
patients or when unusual features raise diagnostic doubts. These features generally include
a normal serum complement early in the disease, or a persisting low complement more
than one month after the onset of the acute nephritic syndrome. Clinical presentations
with proteinuria in the nephrotic range or developing rapidly progressive renal failure are
rare enough in APSGN that histopathological confirmation of the diagnosis is essential.

Pathology of Acute Post-Streptococcal Glomerulonephritis

Light microscopic findings
The majority of cases (including 72% in a recently published series of adult patients (Nasr,
et al., 2008)) show diffuse proliferative and exudative glomerulonephritis (GN). The
glomeruli in these cases are often enlarged and show global endocapillary hypercellularity
with variable and often large numbers of neutrophils, as shown in Figures 1 and 2. Most of
the remaining cases show focal proliferative and exudative GN, or predominantly
mesangial proliferative GN, while a membranoproliferative GN (MPGN) pattern is rarely
seen (Montseny, Meyrier, Kleinknecht, & Callard, 1995; Nasr, et al., 2008; Rosenberg, et
al., 1985; Silva, 2005). When a Masson’s trichrome stain is performed, fuschinophilic, red-
orange subepithelial, and mesangial deposits may be evident. Crescents, primarily
segmental cellular crescents, are present in up to half of cases, and may be accompanied
by segmental fibrinoid necrosis with disruption of the glomerular basement membrane
(GBM) that is evident on a silver methenamine stain (Nasr, et al., 2008; Montseny,
Meyrier, Kleinknecht, & Callard, 1995).
After the first 1-2 weeks of the disease, there is a progressive decline in cellularity, initially
from the loss of the neutrophils, which results in a combined mesangial and endocapillary
10 Streptococcus pyogenes

Figure 1. Acute post-streptococcal glomerulonephritis (GN) with severe proliferative and exudative GN.
The glomerulus is enlarged and markedly hypercellular with a large number of neutrophils. Note the red
blood cells in some tubular lumens. Hematoxylin and eosin (H & E) stain, original magnification x200.

proliferative GN. At this stage, the histologic appearance of the glomeruli may resemble
that of an early MPGN. Over the ensuing weeks, endocapillary hypercellularity is lost,
resulting in a predominantly mesangial proliferative GN that is visible by light
microscopy.
In the acute phase of the disease, interstitial inflammation, which is typically comprised of
a mixture of lymphocytes, monocytes, plasma cells, and neutrophils, is present in most
cases. Focal intratubular neutrophils are not infrequent, with these cells coming from the
inflamed glomeruli. In the study by Nasr et al. (Nasr, et al., 2008), histologic evidence of
acute tubular injury, characterized by the flattening of proximal tubular epithelium with
loss of brush borders and nuclear enlargement, was seen in 60% of cases. Mild to
moderate arteriosclerosis was also seen in the majority of these adult cases; cases with
Post-Streptococcal Glomerulonephritis 11

Figure 2. Acute post-streptococcal GN with proliferative and exudative GN. The glomerulus shows
endocapillary hypercellularity with multiple neutrophils, although far fewer than the glomerulus in Figure
1. Periodic acid-Schiff (PAS) stain, original magnification x400.

underlying diabetic nephropathy tended to have more frequent and more severe
arteriosclerosis, as well as arteriolar hyalinization and thickening (Nasr, et al., 2008).

Immunofluorescence Microscopy
Immunofluorescence findings in evolving stages of post-streptococcal GN have been
elegantly defined by Sorger et al. (Sorger, et al., 1982). In the early phase of the disease (the
initial 2–3 weeks), the glomeruli show finely granular deposits of C3 and usually IgG in
the capillary walls and mesangial areas, in what has been termed a “starry sky” pattern (as
shown in Figure 3. Later in the disease, with resorption of many of the capillary wall
deposits, there is a predominantly mesangial pattern of staining with a predominance of
C3. In reality, not all of the deposits that contribute to the mesangial pattern are actually
12 Streptococcus pyogenes

Figure 3. Immunofluorescence staining for C3 in acute post-streptococcal GN. There is granular staining in
the glomerular capillary walls and mesangium, in a “starry-sky” pattern. Fluorescein isothiocyanate (FITC)
conjugated anti-human C3, original magnification x400.

within the mesangium; as discussed below, many are subepithelial deposits within the
mesangial “waist” that are resorbed more slowly than deposits in peripheral portions of
the glomerular capillaries. A third pattern of staining, characterized by coarse granular to
confluent granular staining along the glomerular capillary walls and termed the “garland”
pattern, is most often seen early in the disease, but may be seen later as well (Sorger, et al.,
1982). It is this pattern that best shows the individual subepithelial “humps” that are the
characteristic ultrastructural feature of this disease.
Post-Streptococcal Glomerulonephritis 13

In acute (and subacute) post-streptococcal GN, deposits of C3 are invariably present,

accompanied by IgG in most cases, and by IgM in approximately 50%, although the latter
staining tends to be of low intensity (Nasr, et al., 2008; Silva, 2005). IgA staining is
uncommon and of low intensity when present, although IgA is often the dominant
immunoglobulin present in post-staphylococcal GN (Nasr, et al., 2008; Haas, Racusen, &
Bagnasco, 2008; Nasr, et al., 2003). Nasr et al. (Nasr, et al., 2008) found C1q staining,
typically of low intensity, in approximately one-third of their cases. Staining for kappa and
lambda light chains mirrors that for IgG, with respect to patterns that have similar
staining intensity for both light chains. Focal and segmental blotchy to amorphous
staining for fibrinogen, most typically at the periphery of glomerular tufts, is frequently
noted within cellular crescents when these are present.

Electron Microscopy
The characteristic ultrastructural finding of acute poststreptococcal GN is the presence of
large subepithelial electron-dense deposits with a “hump-like” appearance, as shown in
Figure 4. The number of these deposits varies considerably between different cases; they
can be quite segmental or rather numerous, although not so much so as to suggest a
membranous nephropathy. The size of the subepithelial “humps” may also vary
considerably within any given glomerulus. In early post-infectious lesions, these deposits
are distributed at various points along glomerular capillaries, although even at this stage,
there is some tendency for the greatest number of deposits to be concentrated at or near
the glomerular basement membrane reflection over mesangial areas (the mesangial
“waist” or “notch,” which can be seen in Figure 5), a finding first noted by Heptinstall
(Heptinstall, 1974). In subacute and resolving cases, the fraction of subepithelial deposits
localized to mesangial “waist” areas increases as more peripheral deposits are resorbed
(Nasr, et al., 2008; Sorger, et al., 1982; Haas, 2003). Mesangial deposits are present in the
great majority of cases of acute poststreptococcal GN and may be abundant, and show
subendothelial deposits in most cases, although these tend to be small and segmental
(Nasr, et al., 2008; Silva, 2005). Extraglomerular deposits are not a feature of this disease.

Treatment
If infection is present at the time of diagnosis, it should be treated. In epidemic situations
and in high-risk communities, the administration of preventive antibiotic treatment to
household members of index cases has been shown to decrease the number of cases of
APSGN (Johnston, Carapetis, Patel, Wallace, & Spillane, 1999).
Patients with an acute nephritic syndrome require restriction of sodium and fluid intake.
For more than three decades, loop diuretics have been known to accelerate the resolution
of edema and improve hypertension (Powell, McCredie, & Rotenberg, 1980). Thiazide
diuretics are ineffective and aldosterone antagonists carry the risk of hyperkalemia. In
cases with severe hypertension, nifedipine may be useful. Angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers carry the risk of hyperkalemia. Nitroprusside
may be needed to treat hypertensive encephalopathy, but only in exceptional cases.
14 Streptococcus pyogenes

Figure 4. Electron-microscopy in acute post-streptococcal GN. Note the large, “hump”-like subepithelial
deposit. The periphery of this deposit is slightly less electron-dense than its center, indicating very early
resorption. The glomerular capillary with the subepithelial “hump” also contains a small subendothelial
deposit. The glomerular basement membranes themselves are unremarkable and the podocyte foot
processes are partially effaced. Uranyl acetate and lead citrate stain, original magnification x7500.

Pulmonary edema may complicate the clinical course and should be treated with oxygen,
loop diuretics, and rotating tourniquets. Digitalis is ineffective and carries an increased
risk of intoxication. Rare complications in APSGN include posterior reversible
leukoencephalopathy (Ahn & Ingulli, 2008) and immune-mediated pneumonitis (Wiles,
et al., 2011). Hemodialysis and peritoneal dialysis may also be required to treat azotemia,
hyperkalemia, or severe circulatory congestion.
Post-Streptococcal Glomerulonephritis 15

Figure 5. Electron microscopy in subacute post-streptococcal GN. A large, “hump”-like subepithelial

deposit is present in a mesangial waist region; deposits are also present within the adjacent mesangial
matrix. Uranyl acetate and lead citrate stain, original magnification x6000.

Crescentic APSGN with a rapidly progressive clinical course has improved in isolated
reports in association with the treatment with intravenous pulses of methylprednisolone;
however, the real benefit of intravenous steroids, immunosuppression, or anticoagulation
remains unproven (Zaffanello, Cataldi, Franchini, & Fanos, 2010).

Prognosis
The short-term prognosis of APSGN in children is excellent; but in adults, and
particularly in debilitated adults, the mortality rate can be as high as 30%, as a
consequence of a cardiovascular complication (Melby, Musick, Luger, & Khanna, 1987).
16 Streptococcus pyogenes

The long-term prognosis, as related to the development of chronic kidney disease, is also
different in children and in adults. In a recent study of a specific outbreak of PSGN that
resulted from the consumption of cheese contaminated with Streptococcus zooepidemicus
and that affected mostly adults, there was an alarming incidence of chronic renal disease:
impaired renal function was found in 30% of the patients after 2 years of follow-up (10%
of them in chronic dialysis therapy) (Pinto, Sesso, Vasconcelos, Watanabe, & Pansute,
2001). In a particular subgroup of adult patients with APSGN that had massive
proteinuria as the initial manifestation of the disease, the long-term prognosis was
especially severe, with an incidence of chronic renal failure as high as 77% (Vogl, Renke,
Mayer-Eichberger, Schmitt, & Bohle, 1986). The worse prognosis in adults has been
attributed to age-related impairment of the Fc-receptor function of the mononuclear
phagocyte system (Mezzano, et al., 1991). Deficiency of the complement factor H-related
protein 5 has also been proposed as a factor that may result in a predisposition to the
development of chronic renal disease (Vernon, et al., 2012).
Regarding the long-term prognosis of APSGN in children, initial reports in 1930 and
1940 indicated an excellent prognosis, but follow-up periods were relatively short.
Subsequent studies have produced widely contrasting results, with the incidence of
abnormal laboratory findings ranging from 3.5% (Potter, Lipschultz, Abidh, Poon-King, &
Earle, 1982) to 60% (Baldwin, Gluck, Schacht, & Gallo, 1974). Discrepancies may partially
result from the different prognosis of PSGN in adults and in children, which is not always
taken into account in the reported series. Studies by Gallo et al. (Gallo, et al., 1980) in the
1980s reported that the incidence of glomerular sclerosis and fibrosis is nearly 50%, but
the clinical relevance of these histological characteristics is uncertain. A revision of the
follow-up studies in children 10-20 years after the acute episodes found that while
approximately 20% of the patients had an abnormal urinalysis or creatinine clearance, less
than 1% had developed end-stage kidney disease. Our own data (Rodríguez-Iturbe &
Musser, 2008), which includes 110 children with epidemic and sporadic PSGN followed
prospectively over 15–18 years after the acute episode, indicate an incidence of 7.2% of
proteinuria, 5.4% of microhematuria, 3.0% of arterial hypertension, and 0.9% of azotemia.
These values are essentially similar to those found in the general population. We have also
followed 10 cases of subclinical PSGN for 10–11 years, and the prognosis is excellent. In
specific communities, such as in Australian aboriginal groups, it has been found that
patients who had APSGN have an increased risk for albuminuria (adjusted odds ratio
(OR) of 6.1, 95% confidence interval (CI) of 2.2–16.9) and hematuria (OR of 3.7, 95% CI
of 1.8–8.0) in relation to controls who did not have APSGN (Hoy, et al., 1998). Finally, the
long-term prognosis of APSGN may be influenced by the coexistence of other risk factors
of chronic renal failure. In patients with a history of APSGN, the association (two-hit)
with both diabetes and metabolic syndrome are likely responsible for the high incidence
of endstage renal disease in aboriginal communities in Northern Australia (White, Hoy, &
McCredie, 2001; Hoy, et al., 2012). It has been reported that persisting arterial stiffness, as
determined by brachial–ankle pulse wave velocity, is found in patients with APSGN who
develop chronic renal disease (Yu, Yu, Yu, Lee, & Huang, 2011).
Post-Streptococcal Glomerulonephritis 17

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